Genetic variation in MHC proteins is associated with T cell receptor expression biases

Jonathan Pritchard, Christopher Garcia and colleagues examine associations between different T cell receptor V genes and MHC alleles by eQTL mapping. They find that there are strong associations between MHC variation and T cell receptor gene usage and map these signals to specific MHC amino acids, m...

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Published in:	Nature genetics Vol. 48; no. 9; pp. 995 - 1002
Main Authors:	Sharon, Eilon, Sibener, Leah V, Battle, Alexis, Fraser, Hunter B, Garcia, K Christopher, Pritchard, Jonathan K
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01.09.2016 Nature Publishing Group
Subjects:	38/39 38/43 45/91 631/208/199 631/208/205/2138 631/208/248 631/250/248 Agriculture Amino acids Analysis Animal Genetics and Genomics Bias Biomedicine Cancer Research Cohort Studies Gene expression Gene Function Gene mapping Genes Genetic diversity Genetic variation Genetic Variation - genetics Genomes Genotype & phenotype Health aspects High-Throughput Nucleotide Sequencing Human Genetics Humans Identification and classification Immunoglobulin Variable Region - genetics Immunoglobulin Variable Region - metabolism Lymphocytes Major Histocompatibility Complex - physiology Membrane proteins Peptides Properties Proteins Quantitative Trait Loci Receptors, Antigen, T-Cell - genetics Receptors, Antigen, T-Cell - metabolism Scholarships & fellowships T cell receptors
ISSN:	1061-4036, 1546-1718, 1546-1718
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Abstract	Jonathan Pritchard, Christopher Garcia and colleagues examine associations between different T cell receptor V genes and MHC alleles by eQTL mapping. They find that there are strong associations between MHC variation and T cell receptor gene usage and map these signals to specific MHC amino acids, many of which physically interact with germline-encoded amino acids on the T cell receptor. In each individual, a highly diverse T cell receptor (TCR) repertoire interacts with peptides presented by major histocompatibility complex (MHC) molecules. Despite extensive research, it remains controversial whether germline-encoded TCR–MHC contacts promote TCR–MHC specificity and, if so, whether differences exist in TCR V gene compatibilities with different MHC alleles. We applied expression quantitative trait locus (eQTL) mapping to test for associations between genetic variation and TCR V gene usage in a large human cohort. We report strong trans associations between variation in the MHC locus and TCR V gene usage. Fine-mapping of the association signals identifies specific amino acids from MHC genes that bias V gene usage, many of which contact or are spatially proximal to the TCR or peptide in the TCR–peptide–MHC complex. Hence, these MHC variants, several of which are linked to autoimmune diseases, can directly affect TCR–MHC interaction. These results provide the first examples of trans -QTL effects mediated by protein–protein interactions and are consistent with intrinsic TCR–MHC specificity.
AbstractList	In each individual, a highly diverse T cell receptor (TCR) repertoire interacts with peptides presented by major histocompatibility complex (MHC) molecules. Despite extensive research, it remains controversial whether germline-encoded TCR-MHC contacts promote TCR-MHC specificity and, if so, whether differences exist in TCR V gene compatibilities with different MHC alleles. We applied expression quantitative trait locus (eQTL) mapping to test for associations between genetic variation and TCR V gene usage in a large human cohort. We report strong trans associations between variation in the MHC locus and TCR V gene usage. Fine-mapping of the association signals identifies specific amino acids from MHC genes that bias V gene usage, many of which contact or are spatially proximal to the TCR or peptide in the TCR-peptide-MHC complex. Hence, these MHC variants, several of which are linked to autoimmune diseases, can directly affect TCR-MHC interaction. These results provide the first examples of trans-QTL effects mediated by protein-protein interactions and are consistent with intrinsic TCR-MHC specificity.In each individual, a highly diverse T cell receptor (TCR) repertoire interacts with peptides presented by major histocompatibility complex (MHC) molecules. Despite extensive research, it remains controversial whether germline-encoded TCR-MHC contacts promote TCR-MHC specificity and, if so, whether differences exist in TCR V gene compatibilities with different MHC alleles. We applied expression quantitative trait locus (eQTL) mapping to test for associations between genetic variation and TCR V gene usage in a large human cohort. We report strong trans associations between variation in the MHC locus and TCR V gene usage. Fine-mapping of the association signals identifies specific amino acids from MHC genes that bias V gene usage, many of which contact or are spatially proximal to the TCR or peptide in the TCR-peptide-MHC complex. Hence, these MHC variants, several of which are linked to autoimmune diseases, can directly affect TCR-MHC interaction. These results provide the first examples of trans-QTL effects mediated by protein-protein interactions and are consistent with intrinsic TCR-MHC specificity. Within each individual, a highly diverse T cell receptor (TCR) repertoire interacts with peptides presented by major histocompatibility complex (MHC) molecules. Despite extensive research, it remains controversial whether germline-encoded TCR-MHC contacts promote TCR-MHC specificity and if so, whether there exist differences in TCR V-gene compatibilities with different MHC alleles. We applied eQTL mapping to test for associations between genetic variation and TCR V-gene usage in a large human cohort. We report strong trans associations between variation in the MHC locus and TCR V-gene usage. Fine mapping of the association signals reveals specific amino acids in MHC genes that bias V-gene usage, many of which contact or are spatially proximal to the TCR or peptide. Hence, these MHC variants, several of which are linked to autoimmune diseases, can directly affect TCR-MHC interaction. These results provide the first examples of trans-QTLs mediated by protein-protein interactions, and are consistent with intrinsic TCR-MHC specificity. In each individual, a highly diverse T cell receptor (TCR) repertoire interacts with peptides presented by major histocompatibility complex (MHC) molecules. Despite extensive research, it remains controversial whether germline-encoded TCR-MHC contacts promote TCR-MHC specificity and, if so, whether differences exist in TCR V gene compatibilities with different MHC alleles. We applied expression quantitative trait locus (eQTL) mapping to test for associations between genetic variation and TCR V gene usage in a large human cohort. We report strong trans associations between variation in the MHC locus and TCR V gene usage. Fine-mapping of the association signals identifies specific amino acids from MHC genes that bias V gene usage, many of which contact or are spatially proximal to the TCR or peptide in the TCR-peptide-MHC complex. Hence, these MHC variants, several of which are linked to autoimmune diseases, can directly affect TCR-MHC interaction. These results provide the first examples of trans-QTL effects mediated by protein-protein interactions and are consistent with intrinsic TCR-MHC specificity. Jonathan Pritchard, Christopher Garcia and colleagues examine associations between different T cell receptor V genes and MHC alleles by eQTL mapping. They find that there are strong associations between MHC variation and T cell receptor gene usage and map these signals to specific MHC amino acids, many of which physically interact with germline-encoded amino acids on the T cell receptor. In each individual, a highly diverse T cell receptor (TCR) repertoire interacts with peptides presented by major histocompatibility complex (MHC) molecules. Despite extensive research, it remains controversial whether germline-encoded TCR–MHC contacts promote TCR–MHC specificity and, if so, whether differences exist in TCR V gene compatibilities with different MHC alleles. We applied expression quantitative trait locus (eQTL) mapping to test for associations between genetic variation and TCR V gene usage in a large human cohort. We report strong trans associations between variation in the MHC locus and TCR V gene usage. Fine-mapping of the association signals identifies specific amino acids from MHC genes that bias V gene usage, many of which contact or are spatially proximal to the TCR or peptide in the TCR–peptide–MHC complex. Hence, these MHC variants, several of which are linked to autoimmune diseases, can directly affect TCR–MHC interaction. These results provide the first examples of trans -QTL effects mediated by protein–protein interactions and are consistent with intrinsic TCR–MHC specificity.
Audience	Academic
Author	Pritchard, Jonathan K Battle, Alexis Sharon, Eilon Fraser, Hunter B Sibener, Leah V Garcia, K Christopher
AuthorAffiliation	3 Department of Molecular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA 4 Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA 7 Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA 5 Immunology Program, Stanford University, Stanford, CA 94305, USA 2 Department of Biology, Stanford University, Stanford, CA 94305, USA 1 Department of Genetics, Stanford University, Stanford, CA 94305, USA 6 Department of Computer Science, Johns Hopkins University, Baltimore, MD 21218, USA
AuthorAffiliation_xml	– name: 4 Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA – name: 2 Department of Biology, Stanford University, Stanford, CA 94305, USA – name: 3 Department of Molecular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA – name: 7 Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA – name: 5 Immunology Program, Stanford University, Stanford, CA 94305, USA – name: 1 Department of Genetics, Stanford University, Stanford, CA 94305, USA – name: 6 Department of Computer Science, Johns Hopkins University, Baltimore, MD 21218, USA
Author_xml	– sequence: 1 givenname: Eilon orcidid: 0000-0002-1262-350X surname: Sharon fullname: Sharon, Eilon organization: Department of Genetics, Stanford University, Department of Biology, Stanford University – sequence: 2 givenname: Leah V surname: Sibener fullname: Sibener, Leah V organization: Department of Molecular Physiology, Stanford University School of Medicine, Department of Structural Biology, Stanford University School of Medicine, Immunology Program, Stanford University – sequence: 3 givenname: Alexis orcidid: 0000-0002-5287-627X surname: Battle fullname: Battle, Alexis organization: Department of Computer Science, Johns Hopkins University – sequence: 4 givenname: Hunter B surname: Fraser fullname: Fraser, Hunter B organization: Department of Biology, Stanford University – sequence: 5 givenname: K Christopher surname: Garcia fullname: Garcia, K Christopher email: kcgarcia@stanford.edu organization: Department of Molecular Physiology, Stanford University School of Medicine, Department of Structural Biology, Stanford University School of Medicine, Howard Hughes Medical Institute, Stanford University – sequence: 6 givenname: Jonathan K surname: Pritchard fullname: Pritchard, Jonathan K email: pritch@stanford.edu organization: Department of Genetics, Stanford University, Department of Biology, Stanford University, Howard Hughes Medical Institute, Stanford University
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/27479906$$D View this record in MEDLINE/PubMed
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Snippet	Jonathan Pritchard, Christopher Garcia and colleagues examine associations between different T cell receptor V genes and MHC alleles by eQTL mapping. They find... In each individual, a highly diverse T cell receptor (TCR) repertoire interacts with peptides presented by major histocompatibility complex (MHC) molecules.... Within each individual, a highly diverse T cell receptor (TCR) repertoire interacts with peptides presented by major histocompatibility complex (MHC)...
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SubjectTerms	38/39 38/43 45/91 631/208/199 631/208/205/2138 631/208/248 631/250/248 Agriculture Amino acids Analysis Animal Genetics and Genomics Bias Biomedicine Cancer Research Cohort Studies Gene expression Gene Function Gene mapping Genes Genetic diversity Genetic variation Genetic Variation - genetics Genomes Genotype & phenotype Health aspects High-Throughput Nucleotide Sequencing Human Genetics Humans Identification and classification Immunoglobulin Variable Region - genetics Immunoglobulin Variable Region - metabolism Lymphocytes Major Histocompatibility Complex - physiology Membrane proteins Peptides Properties Proteins Quantitative Trait Loci Receptors, Antigen, T-Cell - genetics Receptors, Antigen, T-Cell - metabolism Scholarships & fellowships T cell receptors
Title	Genetic variation in MHC proteins is associated with T cell receptor expression biases
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